PTEN c.703G>T, p.Glu235Ter
NM_000314.8:c.703G>T
COSMIC ID: COSM5292
Pathogenic
This nonsense variant results in PTEN loss of function supported by PVS1 Very Strong, functional reduction (PS3 Moderate), absence from population databases (PM2 Supporting), and computational splicing impact (PP3 Supporting), consistent with a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.703G>T
Protein Change
E235*
Location
Exon 7
(Exon 7 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5292
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.703G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Not Classified
Publications (0)
No publication details.
Clinical Statement
Present in ClinVar, however no clinical evidence available for this variant.
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The PTEN E235* variant is a truncating mutation that results in a premature stop codon, leading to a loss of PTEN phosphatase function. Functional studies indicate that this variant reduces phosphatase activity, impairs the ability to negatively regulate the PI3K/AKT pathway, and increases genomic instability. These findings support a damaging effect of the PTEN E235* variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines for PTEN, the rule for PVS1 Very Strong Strength is: 'Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: a truncating nonsense variant expected to cause loss of function, located outside the last exon of PTEN. Therefore, this criterion is applied at Very Strong strength because it fulfills the PTEN PVS1 decision tree for null variants resulting in LOF.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PS1 Strong Strength is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.' The evidence for this variant shows: no prior PTEN variant reported with the same amino acid change or position. Therefore, this criterion is not applied at Not Applied strength because the variant does not match an established pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PS2 Very Strong Strength is: 'Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.' The evidence for this variant shows: no reported de novo occurrence data. Therefore, this criterion is not applied at Not Applied strength because de novo evidence is lacking.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing guidelines, the finding for PS3 is: 'Applied PS3_Moderate (Score -3.3226 < -1.11)'. The evidence for this variant shows: functional studies demonstrate reduced phosphatase activity with a score of -3.3226. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN-specific PS3 Moderate threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PS4 Strong Strength is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.' The evidence for this variant shows: no case-control or affected individual frequency data. Therefore, this criterion is not applied at Not Applied strength because prevalence data are unavailable.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM1 Moderate Strength is: 'Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168.' The evidence for this variant shows: residue 235 is outside these defined hotspots. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a PTEN hotspot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM2 Supporting Strength is: 'Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.' The evidence for this variant shows: variant absent from gnomAD (MAF=0). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 Moderate Strength is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: PTEN is associated with dominant inheritance and no trans-occurrence data. Therefore, this criterion is not applied at Not Applied strength because PM3 is not relevant for a dominantly inherited gene.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 Moderate Strength is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: a nonsense variant leading to protein truncation, not an in-frame indel or stop-loss. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet PM4 criteria.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM5 Moderate Strength is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: the variant is a nonsense change, not a missense. Therefore, this criterion is not applied at Not Applied strength because PM5 applies only to missense variants.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for PM6 Moderate Strength is: 'Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied at Not Applied strength because de novo status is not reported.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 Supporting Strength is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation data are lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 Supporting Strength is: 'Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: the variant is a nonsense change, not a missense. Therefore, this criterion is not applied at Not Applied strength because PP2 applies only to missense variants.
PP3
PP3 (Supporting)
According to VCEP guidelines for PTEN, the rule for PP3 Supporting Strength is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak.' The evidence for this variant shows: SpliceAI predicts a high splicing impact (0.83). Therefore, this criterion is applied at Supporting strength because computational predictions indicate a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 Supporting Strength is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied at Not Applied strength because specific phenotype information is unavailable.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 Supporting Strength is: 'Reputable source reports variant as pathogenic.' The evidence for this variant shows: no ClinVar or other definitive pathogenic assertions. Therefore, this criterion is not applied at Not Applied strength because no authoritative external pathogenic classification is available.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BA1 Stand Alone Strength is: 'gnomAD Filtering allele frequency >0.00056 (0.056%).' The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied at Not Applied strength because allele frequency is below the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS1 Strong Strength is: 'gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).' The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied at Not Applied strength because allele frequency is below BS1 range.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS2 Strong Strength is: 'Observed in the homozygous state in a healthy or PHTS-unaffected individual.' The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied at Not Applied strength because BS2 evidence is lacking.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS3 Strong Strength is: 'Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.' The evidence for this variant shows: functional studies indicate damaging effect. Therefore, this criterion is not applied at Not Applied strength because functional data support deleterious effect.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BS4 Strong Strength is: 'Lack of segregation in affected members of two or more families.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because family segregation has not been assessed.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 Supporting Strength is: 'Missense variant in a gene for which primarily truncating variants are known mechanism of disease.' The evidence for this variant shows: the variant is truncating, not missense. Therefore, this criterion is not applied at Not Applied strength because BP1 applies only to missense variants.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 Supporting Strength is: 'Observed in trans with a pathogenic variant in a dominant gene.' The evidence for this variant shows: no data on cis/trans configuration. Therefore, this criterion is not applied at Not Applied strength because phase information is not available.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 Supporting Strength is: 'In-frame deletions/insertions in a repetitive region without a known function.' The evidence for this variant shows: a nonsense variant, not in-frame. Therefore, this criterion is not applied at Not Applied strength because BP3 applies only to in-frame indels.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN, the rule for BP4 Supporting Strength is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: mixed computational predictions and SpliceAI supports impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 Supporting Strength is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied at Not Applied strength because no alternate etiology is documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 Supporting Strength is: 'Reputable source reports variant as benign.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied at Not Applied strength because no authoritative benign assertion exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 Supporting Strength is: 'Synonymous or intronic variant with no predicted splicing impact.' The evidence for this variant shows: the variant is a nonsense change, not synonymous/intronic. Therefore, this criterion is not applied at Not Applied strength because BP7 applies only to silent/intronic variants.